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Hippocampus-specific deletion of BDNF in adult mice impairs spatial memory and extinction of aversive memories

Molecular Psychiatry volume 12, pages 656–670 (2007)Cite this article

Abstract

Brain-derived neurotrophic factor (BDNF) is known to play a critical role in the synaptic plasticity underlying the acquisition and/or consolidation of certain forms of memory. Additionally, a role has been suggested for neurotrophin function within the hippocampus in protection from anxiety and depressive disorders. Understanding the function of this important gene in adult animals has been limited however, because standard knockouts are confounded by gene effects during development. There are no BDNF receptor-specific pharmacological agents, and infusions of neuropeptides or antibodies have other significant limitations. In these studies, we injected a lentivirus expressing Cre recombinase bilaterally into the dorsal hippocampus in adult mice floxed at the BDNF locus to facilitate the site-specific deletion of the BDNF gene in adult animals. Significant decreases in BDNF mRNA expression are demonstrated in the hippocampi of lenti-Cre-infected animals compared with control lenti-GFP-infected animals. Behaviorally, there were no significant effects of BDNF deletion on locomotion or baseline anxiety measured with startle. In contrast, hippocampal-specific BDNF deletions impair novel object recognition and spatial learning as demonstrated with the Morris water maze. Although there were no effects on the acquisition or expression fear, animals with BDNF deletions show significantly reduced extinction of conditioned fear as measured both with fear-potentiated startle and freezing. These data suggest that the cognitive deficits and impairment in extinction of aversive memory found in depression and anxiety disorders may be directly related to decreased hippocampal BDNF.

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Acknowledgements

Support was provided by NIH (MH069884, KR and MH070218, JPC), NARSAD (KR), NIH/NCRR base grant (P51RR000165) to Yerkes National Primates Research Center and the Center for Behavioral Neuroscience (NSF agreement IBN-987675). We would also like to acknowledge C Todd French, MS, for excellent technical support.

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  1. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA

    S A Heldt, L Stanek, J P Chhatwal & K J Ressler

  2. Center for Behavioral Neuroscience and Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, GA, USA

    S A Heldt, L Stanek, J P Chhatwal & K J Ressler

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Heldt, S., Stanek, L., Chhatwal, J. et al. Hippocampus-specific deletion of BDNF in adult mice impairs spatial memory and extinction of aversive memories. Mol Psychiatry 12, 656–670 (2007). https://doi.org/10.1038/sj.mp.4001957

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Keywords

  • fear
  • brain-derived neurotrophic factor
  • anxiety
  • depression
  • hippocampus
  • Cre-Lox

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